RAR-Immune: A randomised, comparative, prospective, multicentre study of the efficacy of nivolumab + ipilimumab versus pazopanib alone in patients with metastatic or unresectable advanced sarcoma of rare subtype

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Leon Berard

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Mar 2021 → 24 Nov 2025

Decision date (initial)

2024-10-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

INCA · BMS France

External identifiers

EU CT number

2024-513982-38-00

EudraCT number

2020-002821-28

ClinicalTrials.gov

NCT04741438

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

The primary objective is to compare the efficacy (Progression-Free Survival) of nivolumab + ipilimumab versus pazopanib in the treatment of patients with metastatic or unresectable advanced rare sarcomas.

Secondary objectives 11

1. • To determine in both study arms:
2. The Best Overall Response (BOR), the Objective Response Rate (ORR) and the duration of response (DOR);
3. The Time to Treatment Failure (TTF);
4. The Overall Survival (OS);
5. The Quality of Life (QoL);
6. The profile of tolerance.
7. • To determine in the experimental arm:
8. The Progression-Free Survival using the iRECIST (immune Response Evaluation Criteria for Solid Tumours).
9. • Translational objectives will be to:
10. i) Quantify tumour PD-L1 expression and Combined Positive Score (CPS) in patients in both arms
11. ii) Identify the predictive biomarkers of treatment response

Conditions and MedDRA coding

Metastatic or unresectable advanced rare sarcomas

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. I1. Age ≥ 18 years at the day of consenting to the study ;
2. I2. Only histologically confirmed sarcoma of rare subtype, defined as one of the following subtypes: - AS (Angiosarcoma) - ASPS (Alveolar Soft Part Sarcoma) - CCSA (Clear Cell Sarcoma) - DSRCT (Desmoplastic Small Round Cell Tumour) - SEF (Sclerosing Epithelioïd Fibrosarcoma) - PEComa (Perivascular Epithelioid Cell Tumour) - IS (Intimal sarcoma) - EMC (Extraskeletal Myxoid Chondrosarcoma) - SFT (Solitary Fibrous Tumour) - EHE (Epithelioid HemangioEndothelioma) - IMT (Inflammatory Myofibroblastic Tumour) - ES (Epithelioïd sarcoma) - FS (FibroSarcoma) - SMARCA-4 deficient sarcoma - MPNST (Malign Peripheral Nerve Sheath Tumours) - Chordoma; - MC (Mesenchymal Chondrosarcoma) - LGFMS (Low Grade FibroMyxoid sarcoma) - KS (Kaposi’s Sarcoma)
3. I3. Metastatic disease or unresectable locally advanced malignancy that is resistant or refractory to standard therapy or for which standard therapy does not exist or is not considered appropriate by the Investigator ;
4. I4. Measurable disease as per the RECIST version 1.1 ;
5. I5. Previously treated with anthracycline-based regimen except for whom standard therapy does not exist or is not considered appropriate by the Investigator: inclusion in first line is allowed (randomisation will be stratified according to the number of previous treatment lines);
6. I6. ECOG Performance Status of 0 or 1;
7. I7. Patients must have an adequate organ and bone marrow function at baseline;
8. I8. Women of childbearing potential must have a negative serum pregnancy test within 7 days before C1D1
9. I9. Women of childbearing potential must agree to use 1 highly effective form of contraception from the time of the negative pregnancy test up to 3 months after the last dose of study drugs.
10. I10. Ability to understand and willingness for follow-up visits;
11. I11. Covered by a medical insurance;
12. I12. Signed and dated informed consent document indicating that the patient has been informed of all aspects of the trial prior to enrolment.

Exclusion criteria 15

1. E1. Concurrent use of any other approved or investigational antineoplastic agent;
2. E2. Prior or concurrent treatment with any antibody targeting PD1, PDL1, PDL2 or CTLA4;
3. E3. Prior treatment with pazopanib;
4. E4. Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases. Note: Asymptomatic patients with treated CNS lesions are eligible,
5. E5. . Patients using, or requirement to use while on the study, or not respecting the minimal wash-out period of medications listed below:...See the protocol
6. E6. History of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis with the following exceptions: • patients with a history of autoimmune-related hypothyroidism who are on stable thyroid replacement hormone therapy, • patients with controlled Type 1 diabetes mellitus, • patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are eligible provided that they meet the following conditions: o Rash must cover less than 10% of body surface area (BSA). o Disease is well controlled at baseline and only requiring low potency topical steroids. o no acute exacerbations of underlying condition within the previous 12 months requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, high potency or oral steroids;
7. E7. Patients with HIV, active B or C hepatitis infection, or any other active infection.
8. E8. Patients with active tuberculosis;
9. E9. Prior allogeneic bone marrow transplantation or solid organ transplant for another malignancy in the past;
10. E10. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan;
11. E11. Patients with a high-risk of hemorrhage or history of coagulopathy;
12. E12. Any contraindication to nivolumab, to ipilimumab or to pazopanib according to the Summary of Product Characteristics of each drug;
13. E13. History of other malignancy other than study disease (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix) unless the patient has been free of disease for at least 3 years;
14. E14. Patient under tutorship or curatorship of deprived of liberty;
15. E15. Pregnant or breast-feeding woman

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint will be Progression-Free Survival, defined as the time from the date of randomisation to the date of first documented progression or death due to any cause. Patients who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment

Secondary endpoints 10

1. The Best Overall Response will be defined as the best among all overall responses during the trial
2. The Objective Response Rate will be defined as the proportion of patients with a best overall response of CR or PR during the trial.
3. The duration of response will be applied only to patients whose BOR is either CR or PR and will be defined as the time from the date of first documented tumour response to the date of first documented disease progression or death due to underlying cancer. Patients with no event at the time of the analysis will be censored at the date of last adequate tumour assessment.
4. The Time to Treatment Failure will be defined as the time from the date of randomisation to the date of permanent study treatments discontinuation (any cause, including disease progression, treatment toxicity, adverse event, start of any new anticancer therapy, withdrawal of consent and death). Patients without treatment failure at the time of the analysis will be censored at the date of last tumour assessment.
5. The Overall Survival will be defined as the time from the date of randomisation to the date of death due to any cause. Any patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive.
6. The Quality of Life will be assessed using the EORTC QLQ-C30 questionnaire.
7. The tolerance profile will be described through the incidence and severity of drug-related AEs according to the Common Terminology Criteria for Adverse Events (CTCAE) (v5.0)
8. The Progression-Free Survival i-RECIST (in the experimental arm) will be defined as the time from the date of randomisation to the date of first documented progression or death due to any cause.
9. Translational research: Translational research will be conducted by a team from the “Centre de Recherche en Cancérologie of Lyon” (Centre Léon Bérard, Lyon). The objectives are to identify: - biomarkers predicting the therapeutic response for immunotherapy in rare sarcomas - resistance pathways and new targets for immunotherapy in rare sarcomas
10. Exploratory objectives: According to the guidelines from the RECIST working group, efforts should be made to introduce the immune-related Response Criteria in clinical trials in which immunotherapy is used18. In experimental arm, overall response will also be assessed using iRECIST: iPFS, iBOR and iORR. Any documented disease progression (RECIST) will be confirmed 4-6 weeks later.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Leon Berard

Sponsor organisation

Centre Leon Berard

Address

28 Rue Laennec

City

Lyon

Postcode

69008

Country

France

Scientific contact point

Organisation

Centre Leon Berard

Contact name

Dr DUFRESNE Armelle

Public contact point

Organisation

Centre Leon Berard

Contact name

Clinical operation manager

Locations

1 EU/EEA country · 13 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications